Blocking caspase-3-mediated proteolysis of IKK beta suppresses TNF-alpha-induced apoptosis

The transcription factor NF-kappaB is essential for survival of many cell t ypes. However, cells can undergo apoptosis despite the concurrent NF-kappaB activation. It is unknown how the protection conveyed by NF-kappaB is over ridden during apoptosis. We report here that I kappaB kinase (IKK) beta was specifically proteolyzed by Caspase-3-related caspases at aspartic acid re sidues 78, 242, 373, and 546 during tumor necrosis factor (TNF)alpha -induc ed apoptosis. Proteolysis of IKK beta eliminated its enzymatic activity, in terfered with IKK activation, and promoted TNF-alpha killing. Point mutatio ns that abrogate IKK beta proteolysis generated a caspase-resistant IKK bet a mutant, which suppressed TNF-alpha -induced apoptosis. Thus, our study de monstrates that TNF-alpha -induced apoptosis requires caspase-mediated prot eolysis of IKK beta.